Pseudohypoparathyroidism type 1B

Title

Other Names:

PHP1B

Categories:

Congenital and Genetic Diseases; Endocrine Diseases; Kidney and Urinary Diseases

Summary Summary

Pseudohypoparathyroidism type 1B (PHP1B) is a disorder characterized by lack of response (resistance) to parathyroid hormone (PTH) and other hormones such as thyroid-stimulating hormone (TSH). Resistance mainly occurs in the kidneys, causing low blood calcium levels, high blood phosphate levels, and elevated PTH levels. The majority of people with PHP1B also have elevated TSH levels due to TSH resistance.^[1]

Severity can vary considerably, even among affected people in the same family. Symptoms usually begin in childhood due to low calcium levels and include numbness, seizures, tetany, cataracts, and dental problems. Some children have skeletal problems, such as reduced bone mineral density and osteitis fibrosa.^[1]

PHP1B is usually sporadic (not inherited), but familial cases with autosomal dominant inheritance have been reported.^[2] Treatment is lifelong, aiming to normalize calcium and PTH levels with active vitamin D metabolites (alfacalcidol or calcitriol) and calcium supplementation.^[1]

Last updated: 9/22/2016

Symptoms Symptoms

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Pseudohypoparathyroidism	Obligate (present in 100% of cases)
Elevated circulating parathyroid hormone level	Very frequent (present in 80%-99% of cases)
Hyperphosphatemia	Very frequent (present in 80%-99% of cases)
Low urinary cyclic AMP response to PTH administration	Very frequent (present in 80%-99% of cases)
Cataract	Frequent (present in 30%-79% of cases)
Delayed eruption of teeth	Frequent (present in 30%-79% of cases)
Full cheeks	Frequent (present in 30%-79% of cases)
Hypoplasia of dental enamel	Frequent (present in 30%-79% of cases)
Nystagmus	Frequent (present in 30%-79% of cases)
Round face	Frequent (present in 30%-79% of cases)
Short neck	Frequent (present in 30%-79% of cases)
Abdominal symptom	Occasional (present in 5%-29% of cases)
Anxiety	Occasional (present in 5%-29% of cases)
Brachydactyly	Occasional (present in 5%-29% of cases)
Chest pain	Occasional (present in 5%-29% of cases)
Conjunctivitis	Occasional (present in 5%-29% of cases)
Cortical subperiosteal resorption of humeral metaphyses	Occasional (present in 5%-29% of cases)
Depression	Occasional (present in 5%-29% of cases)
Diaphyseal sclerosis	Occasional (present in 5%-29% of cases)
Dyskinesia	Occasional (present in 5%-29% of cases)
Dyspnea	Occasional (present in 5%-29% of cases)
Hypocalcemic tetany	Occasional (present in 5%-29% of cases)
Hyporeflexia	Occasional (present in 5%-29% of cases)
Increased bone density with cystic changes	Occasional (present in 5%-29% of cases)
Irritability	Occasional (present in 5%-29% of cases)
Laryngeal dystonia	Occasional (present in 5%-29% of cases)
Muscle cramps	Occasional (present in 5%-29% of cases)
Myoclonic spasms	Occasional (present in 5%-29% of cases)
Obesity	Occasional (present in 5%-29% of cases)
Paresthesia	Occasional (present in 5%-29% of cases)
Prolonged QT interval	Occasional (present in 5%-29% of cases)
Short metacarpal	Occasional (present in 5%-29% of cases)
Growth hormone deficiency	Very rare (present in 1%-4% of cases)
Hypocalcemic seizures	Very rare (present in 1%-4% of cases)
Pituitary resistance to thyroid hormone	Very rare (present in 1%-4% of cases)
Autosomal dominant inheritance	-
Hypocalcemia	-
Sporadic	-

Last updated: 9/1/2017

Cause Cause

PHP1B is a complex genetic disorder that may be caused by various types of changes in genes or chromosomes. While there are several different PHP1B subtypes, they all appear to somehow be associated with methylation changes involving the region of the GNAS gene.^[3]

Methylation is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. Abnormal methylation can disrupt the normal activity of genes. For example, for genes that are only "active" when inherited from a certain parent, methylation is one way that a gene's parent of origin is "marked" during the formation of egg and sperm cells.^[4] Changes that affect the activation and deactivation of genes without any change in the underlying DNA sequence are called epigenetic changes.^[5]

Epigenetic changes involving PHP1B can be caused by a maternal deletion in the GNAS or STX16 gene, by paternal uniparental isodisomy of chromosome 20q (patUPD20q) or by undefined genetic mutations. The GNAS methylation changes are ultimately responsible for resistance to PTH signals in the proximal renal tubules (part of the kidneys), leading to the features of PHP1B.^[3]

Last updated: 9/22/2016

Inheritance Inheritance

PHP1B is most often sporadic, occurring in people with no family history of PHP1B. However, sex-influenced autosomal dominant inheritance has been reported. When a trait is sex-influenced, it means that the trait is expressed differently depending on whether it is inherited from a person's mother or father.^[2] In familial cases of PHP1B, it appears that parathyroid hormone (PTH) resistance in PHP1B develops only after maternal inheritance of the genetic change, whereas paternal inheritance is not associated with PTH resistance or other endocrine abnormalities.^[2]^[1] In several families with PHP1B, it was reported that the disorder only occurred if the genetic change was inherited from a female carrier; offspring of affected fathers were unaffected.^[2]

The genetics of PHP1B is extremely complex. The disorder may be caused by various types of genetic or epigenetic changes. Because the clinical features of the sporadic and autosomal dominant forms of PHP1B are similar, it has been emphasized by several researchers that a molecular diagnosis (identifying the specific genetic cause in each case) is of great importance for determining specific risks to family members.^[6] People with personal questions or concerns about the inheritance of PHP1B are strongly encouraged to speak with a genetic counselor or other genetics professional. A genetics professional can help by:

thoroughly evaluating the family history
addressing questions and concerns
assessing recurrence risks
facilitating genetic testing if desired
discussing prenatal testing and management options

Last updated: 9/23/2016

Diagnosis Diagnosis

The diagnosis of PHP1B is generally based on clinical features (signs, symptoms, and physical exams) and biochemical findings from a blood test for calcium-phosphate metabolism. This blood test includes measurements of calcium, phosphate, magnesium, and parathyroid hormone (PTH) in order to distinguish PHP from other conditions.^[7] PHP1B can be distinguished from other types of PHP by the absence of Albright's hereditary osteodystrophy.^[7]^[1] Molecular genetic testing can confirm the diagnosis.^[1]

Last updated: 9/22/2016

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Do you have updated information on this condition? Let us know.

Organizations Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

American Thyroid Association
6066 Leesburg Pike, Suite 550
Falls Church, VA 22041
Toll-free: 800–THYROID (849–7643)
Telephone: 703–998–8890
Fax: 703–998–8893
E-mail: admin@thyroid.org
Website: http://www.thyroid.org
Hormone Health Network
Toll-free: 800-HORMONE (1-800-467-6663)
E-mail: hormone@endocrine.org
Website: http://www.hormone.org
Hypopara UK
6 The Meads
East Grinstead
West Sussex, RH19 4DF United Kingdom
Telephone: 01342 316315
E-mail: lizglenister@hypopara.org.uk
Website: http://hypopara.org.uk/home.php
HypoPARAthyroidism Association, Inc. (HPTH )
P.O. Box 2258
Idaho Falls, ID 83403
Toll-free: 866-213-0394
Telephone: +1-208-524-3857
E-mail: jsanders@hypopara.org
Website: https://www.hypopara.org/
The Endocrine Society
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815
Toll-free: 888–363–6274
Telephone: 301–941–0200
Fax: 301–941–0259
E-mail: societyservices@endo-society.org
Website: http://www.endo-society.org

Social Networking Websites

Visit the Pseudohypoparathyroidism Support Group group on Facebook.

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Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Pseudohypoparathyroidism type 1B. Click on the link to view a sample search on this topic.

News & Events News & Events

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Related Diseases Related Diseases

The following diseases are related to Pseudohypoparathyroidism type 1B. If you have a question about any of these diseases, you can contact GARD.

Pseudohypoparathyroidism

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Is the condition hereditary? I have it and my partner is pregnant. See answer
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References References

Giovanna Mantovani. Pseudohypoparathyroidism type 1B. Orphanet. October, 2014; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=94089.
Cassandra L. Kniffin. PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B. OMIM. June 2010; http://omim.org/entry/603233.
Poradosu S, Bravenboer B, Takatani R, Jüppner H. Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus. BMJ Case Rep. May 11, 2016; 2016:
Beckwith-Wiedeman syndrome. Genetics Home Reference. June, 2015; https://ghr.nlm.nih.gov/condition/beckwith-wiedemann-syndrome#genes.
Epigenetics. NHGRI Talking Glossary. https://www.genome.gov/glossary/index.cfm?id=528.
HM LUK, IFM LO, TMF TONG, KKS LAI, STS LAM. Pseudohypoparathyroidism Type 1b: First Case Report in Chinese and Literature Review. HK J Paediatr. 2015; 20:32-36.
Valentina Donghi, Stefano Mora, Ilaria Zamproni, Giuseppe Chiumello and Giovanna Weber. Pseudohypoparathyroidism, an often delayed diagnosis: a case series. Cases Journal. 2009; http://www.casesjournal.com/content/2/1/6734.